Differential expression of uridine phosphorylase in tumors contributes to an improved fluoropyrimidine therapeutic activity

• Published in: Molecular cancer therapeutics 2011-12, Vol.10 (12), p.2330-2339
• Main Authors: Cao, Deliang, Ziemba, Amy, McCabe, James, Yan, Ruilan, Wan, Laxiang, Kim, Bradford, Gach, Michael, Flynn, Stuart, Pizzorno, Giuseppe
• Format: Article
• Language: English
• Subjects: Animals; Antimetabolites, Antineoplastic - metabolism; Antimetabolites, Antineoplastic - therapeutic use; Capecitabine; Cell Line, Tumor; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm - genetics; Fluorouracil - analogs & derivatives; Fluorouracil - metabolism; Fluorouracil - therapeutic use; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - metabolism; Prodrugs - metabolism; Prodrugs - therapeutic use; Pyrimidines - metabolism; Pyrimidines - therapeutic use; Treatment Outcome; Uridine Phosphorylase - genetics; Uridine Phosphorylase - metabolism; Uridine Phosphorylase - physiology
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-11-0202

Abrogation of uridine phosphorylase (UPase) leads to abnormalities in pyrimidine metabolism and host protection against 5-fluorouracil (5-FU) toxicity. We elucidated the effects on the metabolism and antitumor efficacy of 5-FU and capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) in our UPase knockout (UPase(-/-)) model. Treatment with 5-FU (85 mg/kg) or capecitabine (1,000 mg/kg) five days a week for four weeks caused severe toxicity and structural damage to the intestines of wild-type (WT) mice, but not in UPase(-/-) animals. Capecitabine treatment resulted in a 70% decrease in blood cell counts of WT animals, with only a marginal effect in UPase(-/-) mice. UPase expressing colon 38 tumors implanted in UPase(-/-) mice revealed an improved therapeutic efficacy when treated with 5-FU and capecitabine because of the higher maximum tolerated dose for fluoropyrimidines achievable in UPase(-/-) mice. (19)F-MRS evaluation of capecitabine metabolism in tumors revealed similar activation of the prodrug in UPase(-/-) mice compared with WT. In WT mice, approximately 60% of capecitabine was transformed over three hours into its active metabolites, whereas 80% was transformed in tumors implanted in UPase(-/-) mice. In UPase(-/-) mice, prolonged retention of 5'dFUR allowed a proportional increase in tumor tissue. The similar presence of fluorinated catabolic species confirms that dihydropyrimidine dehydrogenase activity was not altered in UPase(-/-) mice. Overall, these results indicate the importance of UPase in the activation of fluoropyrimidines, the effect of uridine in protecting normal tissues, and the role for tumor-specific modulation of the phosphorolytic activity in 5-FU or capecitabine-based chemotherapy.